At present, the most significant known risk factors for schizophrenia are copy number variations (CNVs), with the 22q11 deletion being the most common. It is present in about 1 in 4,000 people and in 1% of people with schizophrenia.
Most cases of 22q11 deletion syndrome (DS) involve a de novo deletion, typically about 3 million base pairs in size, and are not inherited. The disorder has variable presentations and individuals carrying the deletion have about a 25% risk of developing schizophrenia.
Included in the 22q11 deletion is the DGCR8 gene, which has a key role in the biogenesis and maturation of miRNAs to their mature, shortened form. Linda Brzustowicz, M.D., professor, department of genetics, Rutgers University, introduced the concept of canalization, which refers to the robustness of a trait or phenotype and the ability of a phenotype to be expressed regardless of genotypic or environmental variability. She proposed that “miRNAs may be a mechanism of canalization.”
The fact that schizophrenia does not develop in about 75% of people with 22q11-DS may be attributable to the increased capacity of canalized traits to absorb mutational variance. Dr. Brzustowicz presented a model in which 22q11-DS results in DGCR8 haplotype insufficiency, which perturbs the miRNA regulatory system, allowing previously silenced regulatory mutations to alter gene expression. DGCR8 mutations result in a reduction in one or more subsets of miRNA, with the consequence of increased gene expression.
By determining which miRNAs are reduced in the brains of patients with 22q11-DS and applying the canalization hypothesis, it may be possible to predict which genes are likely to have increased expression and to have a role in the development of schizophrenia.
Maria Karayiorgou, M.D., professor of psychiatry at Columbia University, is also studying 22q11 mutations, and specifically the 22q11.2 microdeletion.
Dr. Karayiorgou uses a mouse model of 22q11 CNVs, characterized by deletions on mouse chromosome 16 that correlate to 22q11 CNVs in humans. She applies behavioral assays to study cognitive deficits and has reported deficits in spatial working memory tasks indicative of decreased working memory capacity. These behavioral deficits are associated with DGCR8 deficiency in DGCR8 knockout mice.
The 22q11.2 microdeletion does not appear to affect basal synaptic transmission in mice, but it may affect the activity of neuronal networks in the prefrontal cortex. The mutated mice exhibited reduced synaptic memory in this region of the brain. Dr. Karayiorgou concluded that miRNA dysregulation likely contributes to the cognitive impairment seen in the mouse model by altering short-term synaptic plasticity.